Regulation of gene expression by ribosomal frameshifting

描述(由申请人提供)： 忠实地维持翻译阅读框架是将遗传信息从基因翻译成蛋白质的基本要求。这一规则的例外主要是在RNA病毒中表现出来的，在RNA病毒中，特定的顺式作用的mRNA信号诱导拉长的核糖体改变阅读框架。鉴于许多基本的生物调节机制已经首先在病毒系统中被使用，我们假设程序化的核糖体移码也被用来调节细胞基因的一个重要子集的表达。如果是这样的话，这将代表着我们对蛋白质翻译观点的重大转变，并可能对我们对许多导致出生缺陷、癌症和衰老的潜在原因的理解产生重大影响。提出了支持这一假设的初步研究。这些包括生物信息学、RNA印迹和一套初步的DNA微阵列分析。拟议的研究将扩展DNA微阵列方法，以识别受程序化-1核糖体移码(-1 PRF)调控的细胞mRNAs。总体策略是识别在-1\f25 PRF-1被抑制的条件下特别稳定的细胞mRNA，反之，识别在-1\f25 PRF-1被刺激时不稳定的细胞mRNA。这些实验产生的数据将相互比较，并与我们的包含基因的共识-1\f25 PRF-1信号数据库进行比较，以便确定关于-1\f25 PRF-1在其表达调控中可能扮演的角色的进一步表征的最佳候选者。

DESCRIPTION (provided by applicant): Faithful maintenance of translational reading frame is a basic requirement for translation of genetic information from genes into proteins. Exceptions to this rule have been characterized mostly in RNA viruses, where specific cis-acting mRNA signals induce elongating ribosomes to shift reading frame. Given that many basic biological regulatory mechanisms have been first in viral systems, we hypothesize that programmed ribosomal frameshifting is utilized to regulate the expression of a significant subset of cellular genes as well. If so, this would represent a significant shift in our view of protein translation, and may have significant impact on our understanding of many of the underlying causes of birth defects, cancer and aging. Preliminary studies are presented supporting this hypothesis. These include bioinformatic, RNA-blot, and a preliminary set of DNA microarray analyses. The proposed studies will expand upon a DNA microarray approach to identify cellular mRNAs that are regulated by programmed -1 ribosomal frameshifting (-1 PRF). The overall strategy will be to identify cellular mRNAs that are specifically stabilized under conditions where -1 PRF is inhibited, and conversely, those that are destabilized when -1 PRF is stimulated. The data generated from these experiments will be compared with one another and with our database of consensus -1 PRF signal containing genes in order to identify the best candidates for further characterization with regard to the role that -1 PRF may play in theregulation of their expression.